Leaflet ELREXFIO 40mg / ml solution for injection

ELREXFIO 40 mg/mL solution for injection

ELREXFIO 40 mg/mL solution for injection

One vial contains 44 mg of elranatamab in 1.1 mL (40 mg/mL).

ELREXFIO 40 mg/mL solution for injection

One vial contains 76 mg of elranatamab in 1.9 mL (40 mg/mL).

Elranatamab is an IgG2 kappa bispecific antibody derived from two monoclonal antibodies (mAbs).

Elranatamab is produced using two recombinant Chinese hamster ovary (CHO) cell lines.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear to slightly opalescent, colourless to pale brownish solution, pH of 5.8, and osmolarity ofapproximately 301 mOsm/L.

ELREXFIO is indicated as monotherapy for the treatment of adult patients with relapsed andrefractory multiple myeloma, who have received at least three prior therapies, including animmunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrateddisease progression on the last therapy.

Treatment should be initiated and supervised by physicians experienced in the treatment of multiplemyeloma.

ELREXFIO should be administered via subcutaneous injection by a healthcare professional withadequately trained medical personnel and appropriate medical equipment to manage severe reactions,including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicitysyndrome (ICANS) (see section 4.4).

Prior to initiating treatment, complete blood count should be performed. Any possibility of activeinfections and/or pregnancy in women of child-bearing potential should be ruled out (see sections 4.4and 4.6).

Recommended dosing schedule

The recommended doses are step-up doses of 12 mg on day 1 and 32 mg on day 4, followed by a fulltreatment dose of 76 mg weekly from week 2 to week 24 (see Table 1).

For patients who have received at least 24 weeks of treatment and have achieved a response, thedosing interval should transition to an every two-week schedule. For patients who have received atleast 24 weeks of treatment at the every two week schedule and have maintained the response, thedose interval should transition to an every four week schedule.

ELREXFIO should be administered according to the step-up dosing schedule in Table 1 to reduce theincidence and severity of CRS and ICANS. Due to the risk of CRS and ICANS, patients should bemonitored for signs and symptoms for 48 hours after administration of each of the 2 step-up doses andinstructed to remain within proximity of a healthcare facility (see section 4.4).

Table 1. ELREXFIO dosing schedule

Dosing schedule Week/day Dose

Week 1: day 1 Step-up dose 1 12 mg

Step-up dosinga,b

Week 1: day 4 Step-up dose 2 32 mg

Weekly dosinga,c,d Week 2-24: day 1 Full treatment dose 76 mg once weekly

Every 2 weeks dosingd,e 76 mg once every two

Week 25-48: day 1 Full treatment doseweeks76 mg once every four

Every 4 weeks dosingd,f,g Week 49 onward: day 1 Full treatment doseweeks

a. Pre-treatment medicinal products should be administered prior to the first three doses of ELREXFIO.

b. A minimum of 2 days should be maintained between step-up dose 1 (12 mg) and step-up dose 2 (32 mg).

c. A minimum of 3 days should be maintained between step-up dose 2 (32 mg) and the first full treatment (76 mg) dose.

d. A minimum of 6 days should be maintained between doses.

e. For patients who have achieved a response.

f. For patients who have received at least 24 weeks of treatment at the every two week schedule.

g. For patients who maintained the response.

Note: See Table 5 for recommendations on restarting ELREXFIO after dose delays.

Recommended pre-treatment medicinal products

The following pre-treatment medicinal products should be administered approximately 1 hour prior tothe first three doses of ELREXFIO, which includes step-up dose 1, step-up dose 2, and the first fulltreatment dose as described in Table 1 to reduce the risk of CRS (see section 4.4):

* paracetamol 500 mg orally (or equivalent)

* dexamethasone 20 mg orally or intravenously (or equivalent)

* diphenhydramine 25 mg orally (or equivalent)

Prophylactic antimicrobials and anti-virals should be considered according to local institutionalguidelines (see section 4.4).

Dose modifications based on toxicity

Dose reductions of ELREXFIO are not recommended. Dose delays may be required to managetoxicities (see section 4.4).

See Tables 2 and 3 for recommended actions for adverse reactions of CRS and ICANS, respectively.

See Table 4 for recommended actions for other adverse reactions.

CRS should be identified based on clinical presentation (see section 4.4). Patients should be evaluatedand treated for other causes of fever, hypoxia, and hypotension. Supportive therapy for CRS(including but not limited to anti-pyretic agents, intravenous fluid support, vasopressors, IL-6 or IL-6receptor inhibitors, supplemental oxygen, etc.) should be administered as appropriate. Laboratorytesting to monitor for disseminated intravascular coagulation (DIC), haematology parameters, as wellas pulmonary, cardiac, renal, and hepatic function should be considered.

Table 2. Recommendations for management of CRS

Gradea Presenting symptoms Actions

Grade 1 Temperature ≥ 38 °Cb * Withhold treatment until CRS resolves.c

* Provide supportive therapy.

Grade 2 Temperature ≥ 38 °C with either: * Withhold treatment until CRS resolves.c

* Hypotension responsive to fluid * Provide supportive therapy.and not requiring vasopressors, * Monitor patients daily for 48 hours following theand/or next dose of ELREXFIO. Instruct patients to

* Oxygen requirement of remain within proximity of a healthcare facility.low-flow nasal cannulad orblow-by

Grade 3 Temperature ≥ 38 °C with either: * Withhold treatment until CRS resolves.c(First * Hypotension requiring one * Provide supportive therapy, which may includeoccurrence) vasopressor with or without intensive care.

vasopressin, and/or * Administer pre-treatment medicinal products prior

* Oxygen requirement of to the next dose of ELREXFIO.

high-flow nasal cannulad, * Monitor patients daily for 48 hours following thefacemask, non-rebreather mask, next dose of ELREXFIO. Instruct patients toor Venturi mask remain within proximity of a healthcare facility.

Grade 3 Temperature ≥ 38 °C with either: * Permanently discontinue therapy.(Recurrent) * Hypotension requiring one * Provide supportive therapy, which may includevasopressor with or without intensive care.

vasopressin, and/or

* Oxygen requirement ofhigh-flow nasal cannulad,facemask, non-rebreather mask,or Venturi mask

Grade 4 Temperature ≥ 38 °C with either: * Permanently discontinue therapy.

* Hypotension requiring multiple * Provide supportive therapy, which may includevasopressors (excluding intensive care.vasopressin), and/or

* Oxygen requirement of positivepressure (e.g., continuouspositive airway pressure[CPAP], bilevel positive airwaypressure [BiPAP], intubation,and mechanical ventilation)

a. Based on American society for transplantation and cellular therapy (ASTCT) 2019 grading for CRS.

b. Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked byinterventions such as antipyretics or anti-cytokine therapy.

c. See Table 5 for recommendations on restarting ELREXFIO after dose delays.

d. Low-flow nasal cannula is ≤ 6 L/min, and high-flow nasal cannula is > 6 L/min.

Neurologic toxicities, including ICANS

Other causes of neurologic symptoms should be ruled out. Patients should be immediately evaluatedand treated based on severity. Supportive therapy, which may include intensive care, for severe orlife-threatening neurologic toxicities, should be provided. Patients who experience Grade 2 or higher

ICANS with the previous dose of ELREXFIO should be instructed to remain within proximity of ahealthcare facility and be monitored for signs and symptoms daily for 48 hours following the nextdose.

Table 3. Recommendations for management of ICANS

Gradea Presenting symptomsb Actions

Grade 1 ICE score 7-9c * Withhold treatment until ICANS resolves.e

* Monitor neurologic symptoms and consider

Or depressed level of consciousnessd: consultation with a neurologist for furtherawakens spontaneously. evaluation and management.

* Consider non-sedating, anti-seizuremedicinal products (e.g., levetiracetam) forseizure prophylaxis.

Grade 2 ICE score 3-6c * Withhold treatment until ICANS resolves.e

* Administer dexamethasonef 10 mg

Or depressed level of consciousnessd: intravenously every 6 hours. Continueawakens to voice. dexamethasone use until resolution to Grade1 or less, then taper.

* Monitor neurologic symptoms and considerconsultation with a neurologist and otherspecialists for further evaluation andmanagement.

* Consider non-sedating, anti-seizuremedicinal products (e.g., levetiracetam) forseizure prophylaxis.

* Monitor patients daily for 48 hours followingthe next dose of ELREXFIO. Instructpatients to remain within proximity of ahealthcare facility.

Grade 3 ICE score 0-2c * Withhold treatment until ICANS resolves.e(First * Administer dexamethasonef 10 mgoccurrence) or depressed level of consciousnessd: intravenously every 6 hours. Continueawakens only to tactile stimulus, dexamethasone use until resolution to Grade1 or less, then taper.or seizuresd, either: * Monitor neurologic symptoms and consider

* any clinical seizure, focal or consultation with a neurologist and othergeneralised, that resolves rapidly, or specialists for further evaluation and

* non-convulsive seizures on management.

electroencephalogram (EEG) that * Consider non-sedating, anti-seizureresolve with intervention, medicinal products (e.g., levetiracetam) forseizure prophylaxis.or raised intracranial pressure: * Provide supportive therapy, which mayfocal/local oedema on neuroimagingd include intensive care.

* Monitor patients daily for 48 hours followingthe next dose of ELREXFIO. Instructpatients to remain within proximity of ahealthcare facility.

Grade 3 ICE score 0-2c * Permanently discontinue treatment.(Recurrent) * Administer dexamethasonef 10 mgor depressed level of consciousnessd: intravenously every 6 hours. Continueawakens only to tactile stimulus, dexamethasone use until resolution to Grade1 or less, then taper.or seizuresd, either: * Monitor neurologic symptoms and consider

* any clinical seizure, focal or consultation with a neurologist and othergeneralised, that resolves rapidly, or specialists for further evaluation and

* non-convulsive seizures on management.

electroencephalogram (EEG) that * Consider non-sedating, anti-seizureresolve with intervention, medicinal products (e.g., levetiracetam) forseizure prophylaxis.or raised intracranial pressure: * Provide supportive therapy, which mayfocal/local oedema on neuroimagingd include intensive care.

Grade 4 ICE score 0c * Permanently discontinue treatment.

* Administer dexamethasonef 10 mg

Or, depressed level of consciousnessd intravenously every 6 hours. Continueeither: dexamethasone use until resolution to Grade

* patient is unarousable or requires 1 or less, then taper.

vigorous or repetitive tactile stimuli * Alternatively, consider administration ofto arouse, or methylprednisolone 1 000 mg per day

* stupor or coma, intravenously for 3 days.

* Monitor neurologic symptoms and consideror seizuresd, either: consultation with a neurologist and other

* life-threatening prolonged seizure specialists for further evaluation and(>5 minutes), or management.

* repetitive clinical or electrical * Consider non-sedating, anti-seizureseizures without return to baseline medicinal products (e.g., levetiracetam) forin between, seizure prophylaxis.

* Provide supportive therapy, which mayor motor findingsd: include intensive care.

* deep focal motor weakness such ashemiparesis or paraparesis,or raised intracranial pressure/cerebraloedemad, with signs/symptoms such as:

* diffuse cerebral oedema onneuroimaging, or

* decerebrate or decorticate posturing,or

* cranial nerve VI palsy, or

* papilloedema, or

* Cushing’s triad

Abbreviations: Immune effector cell-associated encephalopathy (ICE).

a. Based on American society for transplantation and cellular therapy (ASTCT) 2019 grading for ICANS.

b. Management is determined by the most severe event, not attributable to any other cause.

c. If patient is arousable and able to perform ICE assessment, assess:

Orientation (oriented to year, month, city, hospital=4 points); Naming (name 3 objects, e.g., point to clock, pen,button=3 points); Following commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue”=1 point);

Writing (ability to write a standard sentence=1 point); and Attention (count backwards from 100 by ten=1 point). If patient isunarousable and unable to perform ICE assessment (Grade 4 ICANS)=0 points.

d. Not attributable to any other cause.

e. See Table 5 for recommendations on restarting ELREXFIO after dose delays.

f. All references to dexamethasone administration are dexamethasone or equivalent medicinal products.

Table 4. Recommended actions for other adverse reactions

Adverse reactions Severity Actions

Haematologic adverse Absolute neutrophil count less than * Withhold treatment untilreactions 0.5 × 109/L absolute neutrophil count is(see section 4.8) 0.5 × 109/L or higher.b

Febrile neutropenia * Withhold treatment untilabsolute neutrophil count is1 × 109/L or higher and feverresolves.b

Haemoglobin less than 8 g/dL * Withhold treatment untilhaemoglobin is 8 g/dL orhigher.b

Platelet count less than 25 000/mcL * Withhold treatment untilplatelet count is 25 000/mcL

Platelet count between 25 000/mcL or higher and no evidence ofand 50 000/mcL with bleeding bleeding.b

Other* non-haematologic Grade 3 or 4 * Withhold treatment untiladverse reactionsa recovery to Grade 1 or less or(see section 4.8) baseline.b

* Permanently discontinue ifrecovery does not occur.

a. Based on National cancer institute common terminology criteria for adverse events (NCI-CTCAE), Version 5.0.

b. See Table 5 for recommendations on restarting ELREXFIO after dose delays (see section 4.2).

* Other than CRS and ICANS.

Restarting ELREXFIO after dose delay

If a dose is delayed, therapy should be restarted based on the recommendations listed in Table 5, andtherapy should be resumed according to the dosing schedule (see Table 1). Pre-treatment medicinalproducts should be administered as indicated in Table 5.

Table 5. Recommendations for restarting therapy with ELREXFIO after dose delay

Last

Duration of delay from the lastadministered Actionadministered dosedose

Step-up dose 1 2 weeks or less (≤ 14 days) Restart at step-up dose 2 (32 mg).a If(12 mg) tolerated, increase to 76 mg 4 days later.

Greater than 2 weeks (> 14 days) Restart step-up dosing schedule at step-updose 1 (12 mg).a

Step-up dose 2 2 weeks or less (≤ 14 days) Restart at 76 mg.a(32 mg)

Greater than 2 weeks to less than or Restart at step-up dose 2 (32 mg).a Ifequal to 4 weeks (15 days and tolerated, increase to 76 mg 1 week later.

≤ 28 days)

Greater than 4 weeks (> 28 days) Restart step-up dosing schedule at step-updose 1 (12 mg).a

Any full 12 weeks or less (≤ 84 days) Restart at 76 mg.

treatment dose(76 mg)

Greater than 12 weeks (> 84 days) Restart step-up dosing schedule at step-updose 1 (12 mg).a If tolerated, increase to76 mg 1 week later.

a. Administer pre-treatment medicinal products prior to the ELREXFIO dose.

Treatment should be continued until disease progression or unacceptable toxicity.

If a dose is missed, the dose should be administered as soon as possible, and the dosing scheduleshould be adjusted to maintain the dosing interval as needed (see Table 1).

No dose adjustment is necessary (see sections 5.1 and 5.2).

No dose adjustment is recommended in patients with mild to moderate renal impairment (estimatedglomerular filtration rate [eGFR] > 30 mL/min/1.73 m2). Limited data are available from patients withsevere renal impairment, see section 5.2.

No dose adjustments are required for mild hepatic impairment (total bilirubin > 1 to 1.5 × ULN andany AST, or total bilirubin ≤ ULN and AST > ULN, see section 5.2).

There is no relevant use of ELREXFIO in the paediatric population for the treatment of multiplemyeloma.

ELREXFIO is for subcutaneous injection only and should be administered by a healthcareprofessional.

The required dose should be injected into the subcutaneous tissue of the abdomen (preferred injectionsite). Alternatively, it may be injected into the subcutaneous tissue of the thigh.

ELREXFIO should not be injected into areas where the skin is red, bruised, tender, hard, or areaswhere there are scars.

For instructions on handling of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered medicinal product should be clearly recorded.

CRS, including life-threatening or fatal reactions, may occur in patients receiving ELREXFIO.

Clinical signs and symptoms of CRS may include, but are not limited to, fever, hypoxia, chills,hypotension, tachycardia, headache, and elevated liver enzymes (see section 4.8).

Therapy should be initiated according to the step-up dosing schedule to reduce risk of CRS andpatients should be monitored following administration of ELREXFIO accordingly. Pre-treatmentmedicinal products should be administered prior to the first three doses to reduce risk of CRS (seesection 4.2).

Patients should be counselled to seek urgent medical attention should signs or symptoms of CRSoccur.

At the first sign of CRS, ELREXFIO should be withheld and patients should be immediately evaluatedfor hospitalisation. CRS should be managed according to the recommendations in section 4.2, andfurther management should be considered per local institutional guidelines. Supportive therapy for

CRS (including but not limited to anti-pyretic agents, intravenous fluid support, vasopressors, IL-6 or

IL-6 receptor inhibitors, supplemental oxygen, etc.) should be administered as appropriate. Laboratorytesting to monitor for disseminated intravascular coagulation (DIC), haematology parameters, as wellas pulmonary, cardiac, renal, and hepatic function should be considered.

Neurologic toxicities, including ICANS

Serious or life-threatening neurologic toxicities, including ICANS, may occur following treatmentwith ELREXFIO (see section 4.8). Patients should be monitored for signs and symptoms (e.g.,decrease level of consciousness, seizures and/or motor weakness) of neurologic toxicities duringtreatment.

Patients should be counselled to seek urgent medical attention should signs or symptoms of neurologictoxicity occur.

At the first sign of neurologic toxicity, including ICANS, ELREXFIO should be withheld andneurology evaluation should be considered. General management for neurologic toxicity (e.g.,

ICANS) is summarised in Table 3 (see section 4.2).

Due to the potential for ICANS, patients should be advised not to drive or operate heavy or potentialdangerous machinery during the step-up dosing schedule and for 48 hours after completing each of the2 step-up doses and in the event of new onset of any neurological symptoms (see sections 4.2 and 4.7).

Severe, life-threatening, or fatal infections have been reported in patients receiving ELREXFIO(see section 4.8). New or reactivated viral infections occurred during therapy with ELREXFIO,including cytomegalovirus infection/reactivation. Progressive multifocal leukoencephalopathy (PML),which can be fatal, has also occurred during therapy with ELREXFIO.

Treatment should not be initiated in patients with active infections. Patients should be monitored forsigns and symptoms of infection prior to and during treatment with ELREXFIO and treatedappropriately. ELREXFIO should be withheld based on the severity of the infection as indicated in

Table 4 for other non-haematologic adverse reactions (see section 4.2).

Prophylactic antimicrobials (e.g., prevention of pneumocystis jirovecii pneumonia) and anti-virals(e.g., prevention of herpes zoster reactivation) should be administered according to local institutionalguidelines.

Neutropenia and febrile neutropenia have been reported in patients receiving ELREXFIO(see section 4.8).

Complete blood cell counts should be monitored at baseline and periodically during treatment.

Treatment with ELREXFIO should be withheld as indicated in Table 4 (see section 4.2). Patients withneutropenia should be monitored for signs of infection. Supportive therapy should be providedaccording to local institutional guidelines.

Hypogammaglobulinemia has been reported in patients receiving ELREXFIO (see section 4.8).

Immunoglobulin levels should be monitored during treatment. Treatment with subcutaneous orintravenous immunoglobulin (IVIG) should be considered if IgG levels fall below 400 mg/dL andpatients should be treated according to local institutional guidelines, including infection precautionsand antimicrobial prophylaxis.

Concomitant use of live viral vaccines

The safety of immunisation with live viral vaccines during or following treatment with ELREXFIOhas not been studied. Vaccination with live virus vaccines is not recommended within the 4 weeksprior to the first dose, during treatment, and at least 4 weeks after treatment.

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially‘sodium-free.’

No interaction studies have been performed with ELREXFIO.

The initial release of cytokines associated with the start of ELREXFIO may suppress cytochrome

P450 (CYP) enzymes. The highest risk of interaction is expected to occur during and up to 14 daysafter the step-up dosing as well as during and up to 14 days after CRS. During this time period,toxicity or medicinal product concentrations should be monitored in patients who are receivingconcomitant sensitive CYP substrates with a narrow therapeutic index (e.g., cyclosporine, phenytoin,sirolimus, and warfarin). The dose of the concomitant medicinal product should be adjusted as needed.

Women of child-bearing potential/Contraception

The pregnancy status of women of child-bearing potential should be verified prior to initiatingtreatment with ELREXFIO.

Women of child-bearing potential should use effective contraception during treatment with

ELREXFIO and for 6 months after the last dose.

There are no human or animal data to assess the risk of elranatamab use during pregnancy. Humanimmunoglobulin (IgG) is known to cross the placenta after the first trimester of pregnancy. Based onthe mechanism of action, elranatamab may cause foetal harm when administered to a pregnant womanand therefore ELREXFIO is not recommended for use during pregnancy.

ELREXFIO is associated with hypogammaglobulinaemia, therefore, assessment of immunoglobulinlevels in newborns of mothers treated with ELREXFIO should be considered.

It is not known whether elranatamab is excreted in human or animal milk, affects breastfed infants oraffects milk production. Human IgGs are known to be excreted in breast milk. A risk to the breastfedchild cannot be excluded and therefore breast-feeding is not recommended during treatment with

ELREXFIO and for 6 months after the last dose.

There are no data on the effect of elranatamab on human fertility. Effects of elranatamab on male andfemale fertility have not been evaluated in animal studies.

ELREXFIO has major influence on the ability to drive and use machines.

Due to the potential for ICANS, patients receiving ELREXFIO are at risk of depressed level ofconsciousness (see section 4.8). Patients should be instructed to refrain from driving or operatingheavy or potential dangerous machinery during and for 48 hours after completing each of the 2 step-updoses and in the event of new onset of neurologic toxicity until resolution of any neurologicalsymptoms (see sections 4.2 and 4.4).

The most frequent adverse reactions are CRS (57.9%), anaemia (54.1%), neutropenia (45.9%), fatigue(44.8%), upper respiratory tract infection (43.2%), injection site reaction (38.3%), diarrhoea (42.1%),pneumonia (38.3%), thrombocytopenia (36.6%), lymphopenia (30.1%), decreased appetite (27.3%),pyrexia (29.0%), rash (27.9%), arthralgia (26.8%), hypokalaemia (23.5%), nausea (21.9%), dry skin(21.9%) and dyspnoea (20.8%).

Serious adverse reactions are pneumonia (31.7%), sepsis (15.8%), CRS (12.6%), anaemia (5.5%),upper respiratory tract infection (5.5%), urinary tract infection (3.8%), febrile neutropenia (3.3%),diarrhoea (2.7%), dyspnoea (2.7%) and pyrexia (2.2%).

Table 6 summarises adverse reactions reported in patients who received ELREXFIO at therecommended dosing regimen (N=183 including 64 patients with prior BCMA-directed antibody drugconjugate [ADC] or chimeric antigen receptor [CAR] T cell therapy [supportive Cohort B]). Themedian duration of treatment was 4.1 (range: 0.03 to 35.9) months. The safety data of ELREXFIO wasalso evaluated in the all-treated population (N=265) with no additional adverse reactions identified.

Adverse reactions are listed according to the MedDRA system organ classification and by frequency.

Frequency categories are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon(≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known(frequency cannot be estimated from the available data). Within each frequency grouping, whererelevant, adverse reactions are presented in order of decreasing seriousness.

Table 6. Adverse reactions in multiple myeloma patients treated with ELREXFIO in

MagnetisMM-3 at the recommended dose

System organ class Adverse reaction Frequency N=183(All grades) Any grade Grade 3(%) or 4 (%)

Infections and infestations Pneumoniaa Very common 38.3 25.7

Sepsisb Very common 18.6 13.1

Upper respiratory tract Very common 43.2 6.0infection

Urinary tract infection Very common 13.7 6.0

Cytomegalovirus Common 9.3 2.2infectionc

Progressive multifocal Uncommon 0.5* 0leukoencephalopathy

Blood and lymphatic Neutropenia Very common 45.9 44.3system disorders Anaemia Very common 54.1 42.6

Thrombocytopenia Very common 36.6 26.2

Lymphopenia Very common 30.1 27.9

Leukopenia Very common 18.6 13.1

Febrile neutropenia Common 3.3 3.3

Immune system disorders Cytokine release Very common 57.9 0.5syndrome

Hypogammaglobulinaemi Very common 16.9 2.7a

Metabolism and nutrition Decreased appetite Very common 27.3 1.1disorders Hypokalaemia Very common 23.5 9.3

Hypophosphataemia Common 6.6 0.5

Nervous system disorders Peripheral neuropathyd Very common 17.5 1.1

Headache Very common 19.7 0

Immune effector cell- Common 3.3 1.1associated neurotoxicitysyndrome (ICANS)

Table 6. Adverse reactions in multiple myeloma patients treated with ELREXFIO in

MagnetisMM-3 at the recommended dose

Respiratory, thoracic and Dyspnoea Very common 20.8 4.9mediastinal disorders

Gastrointestinal disorders Diarrhoea Very common 42.1 2.7

Nausea Very common 21.9 0

Skin and subcutaneous Rashe Very common 27.9 0tissue disorders Dry skin Very common 21.9 0

Musculoskeletal and Arthralgia Very common 26.8 1.6connective tissue disorders

General disorders and Injection site reaction Very common 38.3 0administration site Pyrexia Very common 29.0 3.3conditions

Fatigue Very common 44.8 6.0

Investigations Transaminases increased Very common 17.5 5.5

* Fatal (Grade 5) case reported.

a. Pneumonia includes atypical pneumonia, bronchopulmonary aspergillosis, coronavirus pneumonia, COVID-19pneumonia, lower respiratory tract infection, lower respiratory tract infection bacterial, lower respiratory tractinfection fungal, pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia aspiration,pneumonia bacterial, pneumonia cytomegaloviral, pneumonia fungal, pneumonia haemophilus, pneumoniainfluenzal, pneumonia pneumococcal, pneumonia pseudomonal, pneumonia respiratory syncytial viral, pneumoniaviral.

b. Sepsis includes bacteraemia, campylobacter bacteraemia, device related bacteraemia, device related sepsis,escherichia bacteraemia, escherichia sepsis, klebsiella sepsis, pseudomonal sepsis, sepsis, septic shock,staphylococcal bacteraemia, staphylococcal sepsis, streptococcal sepsis, urosepsis.

c. Cytomegalovirus infection includes cytomegalovirus chorioretinitis, cytomegalovirus gastroenteritis,cytomegalovirus infection, cytomegalovirus infection reactivation, cytomegalovirus viraemia.

d. Peripheral neuropathy includes dysaesthesia, Guillain-Barre syndrome, hypoaesthesia, neuralgia, neuropathyperipheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensoryneuropathy, polyneuropathy.

e. Rash incudes dermatitis exfoliative, dermatitis exfoliative generalised, epidermolysis, erythema, palmar-plantarerythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash pustular,symmetrical drug-related intertriginous and flexural exanthema.

CRS occurred in 57.9% of patients who received ELREXFIO at the recommended dosing schedule,with Grade 1 CRS in 43.7%, Grade 2 in 13.7% and Grade 3 in 0.5% of patients. Most patientsexperienced CRS after the first step-up dose (43.2%) or the second step-up dose (19.1%), with 7.1% ofpatients having CRS after the first full treatment dose and 1.6% of patients after a subsequent dose.

Recurrent CRS occurred in 13.1% of patients. The median time to onset of CRS was 2 (range: 1 to 9)days after the most recent dose, with a median duration of 2 (range: 1 to 19 days) days.

Among patients who developed CRS, associated symptoms included fever (98.1%), hypotension(20.8%), and hypoxia (11.3%) and 34.0% received tocilizumab (or siltuximab) and 15.1% receivedcorticosteroids for treatment of CRS.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

ICANS occurred in 3.3% of patients following treatment with ELREXFIO at the recommended dosingschedule, with Grade 1 ICANS in 0.5%, Grade 2 in 1.6% and Grade 3 in 1.1% of patients. Themajority of patients had ICANS after the first step-up dose (2.7%), 1 (0.5%) patient had ICANS afterthe second step-up dose and 1 (0.5%) patient had ICANS after a subsequent dose. Recurrent ICANSoccurred in 1.1% of patients. The median time to onset was 3 (range: 1 to 4) days after the most recentdose with a median duration of 2 (range: 1 to 18) days.

The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of

CRS. The most frequent symptoms of ICANS included a depressed level of consciousness and

Grade 1 or Grade 2 Immune Effector Cell-Associated Encephalopathy (ICE) scores (see Table 3).

Among patients who developed ICANS, 66.7% received corticosteroids, 33.3% received tocilizumab(or siltuximab), 33.3% received levetiracetam and 16.7% received anakinra for treatment of ICANS.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms and signs

There has been minimal experience of overdose in clinical studies. The maximum tolerated dose ofelranatamab has not been determined. In clinical studies, doses up to 76 mg once weekly have beenadministered.

In the event of an overdose, the patient should be monitored for any signs or symptoms of adversereactions and appropriate supportive treatment should be instituted immediately.

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code:

L01FX32

Elranatamab is a bi-specific T-cell engaging antibody that binds CD3-epsilon on T cells and B-cellmaturation antigen (BCMA) on plasma cells, plasmablasts, and multiple myeloma cells. Binding ofelranatamab to BCMA on tumour cells and CD3 on T cells is independent of native T cell receptor(TCR) specificity or reliance on major histocompatibility (MHC) Class 1 molecules. Elranatamabactivated T cells, led to proinflammatory cytokine release, and resulted in multiple myeloma cell lysis.

During treatment with elranatamab at the recommended dose in the MagnetisMM-3 study, anti-drugantibodies (ADA) were detected in 9.5% participants. No evidence of ADA impact onpharmacokinetics, efficacy or safety was observed; however, data are still limited.

Relapsed or refractory multiple myeloma

The efficacy of ELREXFIO monotherapy was evaluated in patients with relapsed or refractorymultiple myeloma in an open-label, non-randomised, multi-centre, Phase 2 study (MagnetisMM-3).

The study included patients who were refractory to at least one proteasome inhibitor (PI), oneimmunomodulatory agent (IMiD) and one anti-CD38 monoclonal antibody. MagnetisMM-3 included123 patients naïve to prior BCMA-directed therapy (pivotal Cohort A). Patients had measurabledisease by international myeloma working group (IMWG) criteria at enrolment. The study includedpatients with an ECOG score of ≤ 2, adequate baseline bone marrow (absolute neutrophil count≥ 1.0 × 109/L, platelet count ≥ 25 × 109/L, haemoglobin level ≥ 8 g/dL), renal (CrCL ≥ 30 mL/min),and hepatic [aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit ofnormal (ULN)], total bilirubin ≤ 2 × ULN] function, and left-ventricular ejection fraction ≥ 40%.

Patients with smouldering multiple myeloma, active plasma cell leukaemia, amyloidosis, POEMS(polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes)syndrome, stem cell transplant within 12 weeks prior to enrolment, active infections, and clinicallysignificant neuropathies and cardiovascular disease, were excluded from the study.

Patients received subcutaneous administration of ELREXFIO at step-up doses of 12 mg on Day 1 and32 mg on Day 4 of treatment, followed by the first full treatment dose of ELREXFIO (76 mg) on Day8 of treatment. Thereafter, patients received 76 mg once weekly. After 24 weeks, in patients whoachieved an IMWG response category of partial response or better with responses persisting for atleast 2 months, the dosing interval was changed from every week to every 2 weeks, and from every2 weeks to every 4 weeks after at least 24 weeks of 76 mg every 2 weeks dosing (see section 4.2).

Among the 123 patients treated in pivotal Cohort A, the median age was 68 (range: 36 to 89) yearswith 19.5% of patients ≥ 75 years of age. 44.7% were female; 58.5% were White, 13.0% were Asian,8.9% were Hispanic/Latino, and 7.3% were Black. Disease stage (R-ISS) at study entry was 22.8% in

Stage I, 55.3% in Stage II, and 15.4% in Stage III. The median time since initial diagnosis of multiplemyeloma to enrolment was 72.9 (range: 16 to 228) months. Patients had received a median of 5 priorlines of therapy (range: 2 to 22); with 96.0% who received ≥ 3 prior lines of therapy. 96.7% weretriple-class refractory and 95.9% refractory to their last line of therapy. 68.3% received priorautologous stem cell transplantation, and 5.7% received prior allogenic stem cell transplantation.

High-risk cytogenetics [t(4;14), t(14;16), or del(17p)] were present in 25.2% of patients. 31.7% ofpatients had extramedullary disease [presence of any plasmacytoma (extramedullary and/orparamedullary) with a soft-tissue component] by blinded independent central review (BICR) atbaseline.

Efficacy results were based on response rate and duration of response (DOR), as assessed by BICRbased on the IMWG criteria. Efficacy results from pivotal Cohort A are shown in Table 7. The median(range) follow-up from initial dose for responders was 27.9 (3.6, 36.8) months.

Table 7. Efficacy results for MagnetisMM-3 in pivotal Cohort A

BCMA-directed therapynaïve patients(pivotal Cohort A)

All treated (N=123)

Objective response rate (ORR: sCR+CR+VGPR+PR), n (%) 75 (61.0%)(95% CI) (51.8, 69.6)

Stringent complete response (sCR) 20 (16.3%)

Complete response (CR) 26 (21.1%)

Very good partial response (VGPR) 23 (18.7%)

Partial response (PR) 6 (4.9%)

Complete response rate (sCR+CR), n (%) 46 (37.4%)(95% CI) (28.8, 46.6)

Time to first response (months)

Number of responders 75

Median 1.22

Range (0.9, 7.4)

Duration of response (DOR) (months)

Number of responders 75

Median (95% CI) NE (NE, NE)

Rate at 12 months (95% CI) 73.4 (61.4, 82.1)

Rate at 24 months (95% CI) 66.9 (54.4, 76.7)

MRD-negativity ratea in patients achieving CR or sCR andevaluable for MRD (31 of the 46 patients who reached CR/sCR wereevaluable for MRD)

Table 7. Efficacy results for MagnetisMM-3 in pivotal Cohort An (%) 28 (90.3%)95% CI (%) (74.2, 98.0)

Abbreviations: CI=confidence interval; NE=not estimable; MRD=minimal residual disease.

a. By threshold 10-5, next generation sequencing clonoSEQ assay (Adaptive Biotechnologies).

The European Medicines Agency has waived the obligation to submit the results of studies with

ELREXFIO in all subsets of the paediatric population in multiple myeloma (see section 4.2 forinformation on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.

Pharmacokinetic parameters are presented as geometric mean (coefficient of variation [CV]%) forunbound elranatamab unless otherwise specified. The Cmax and AUCtau of elranatamab after the firstsubcutaneous dose increased in a dose proportional manner over the evaluated dose range viasubcutaneous administration (~ 6 to 76 mg). The median accumulation ratio after 24 weeks of weeklydosing relative to the first subcutaneous dose of elranatamab 76 mg for Cmax and AUCtau was 6.6-foldand 11.2-fold, respectively. The predicted Cavg, Cmax, and Ctrough and the observed Ctrough of elranatamabare presented in Table 8.

Table 8. Pharmacokinetic parameters of elranatamab following the recommended dose

Timepoint Parameters

Predicted Observed

Cavg C dmax Ctrough Ctrough(mcg/mL) (mcg/mL) (mcg/mL) (mcg/mL)

End of weekly dose (week 24)a 32.0 (46%) 33.0 (46%) 30.5 (48%) 32.2 (71%)

Steady state (every two weeksa,b 17.7 (53%) 19.5 (51%) 15.1 (60%) 16.5 (59%)dosing)

Steady state (every 4 weeksa,c 8.8 (58%) 11.5 (54%) 5.9 (78%) 6.7 (76%)dosing)

a. Predicted pharmacokinetic parameters are reported for patients who have achieved a response.

b. Predicted steady state exposure of elranatamab every two weeks dose is approximated at week 48.

c. Predicted steady state exposure of elranatamab once every 4 weeks dose is approximated at week 72.

d. Observed elranatamab Ctrough is presented as geometric mean (CV%). Predose concentrations at Cycle 7

Day 1 (n = 40), Cycle 13 Day 1 (n = 23), and Cycle 25 Day 1 (n = 10) represent steady-state Ctrough for weeklydosing, every 2 weeks dosing, and every 4 weeks dosing, respectively.

The predicted mean bioavailability of elranatamab was 56.2% when administered subcutaneously. Themedian Tmax after elranatamab SC administration across all dose levels ranged from 3 to 7 days.

Based on the population pharmacokinetic model, the predicted mean volume of distribution ofunbound elranatamab was 4.78 L, 69% (CV) for the central compartment, and 2.83 L for theperipheral compartment.

The predicted geometric mean half-life of elranatamab is 22, 64% (CV) days at week 24 followingdoses of 76 mg weekly. Based on the population pharmacokinetic model, the predicted meanelranatamab clearance was 0.324 L/day, 100% (CV).

No clinically relevant differences in the pharmacokinetics of elranatamab were observed based on age(36 to 89 years), sex (167 male, 154 female), race (193 White, 49 Asian, 29 Black), and body weight(37 to 160 kg).

No studies of elranatamab in patients with renal impairment have been conducted. Results ofpopulation pharmacokinetic analyses indicate that mild renal impairment (60 mL/min/1.73 m2 ≤ eGFR< 90 mL/min/1.73 m2) or moderate renal impairment (30 mL/min/1.73 m2 ≤ eGFR< 60 mL/min/1.73 m2) did not significantly influence the pharmacokinetics of elranatamab. Limiteddata are available from patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2).

No studies of elranatamab in patients with hepatic impairment have been conducted. Results ofpopulation pharmacokinetic analyses indicate that mild hepatic impairment (total bilirubin > 1 to 1.5 ×

ULN and any AST, or total bilirubin ≤ ULN and AST > ULN) did not significantly influence thepharmacokinetics of elranatamab. No data are available in patients with moderate (total bilirubin > 1.5to 3.0 × ULN and any AST) or severe (total bilirubin > 3.0 × ULN and any AST) hepatic impairment.

No animal studies have been performed to assess the carcinogenic or genotoxic potential ofelranatamab.

Reproductive toxicology and fertility

No animal studies have been performed to evaluate the effects of elranatamab on fertility orreproduction and foetal development.

In a 13-week repeat-dose toxicity study in sexually mature cynomolgus monkeys, there were nonotable effects on male and female reproductive organs following subcutaneous doses up to6 mg/kg/week (approximately 6.5 times the maximum recommended human dose, based on AUCexposure).

Edetate disodium

L-histidine

L-histidine hydrochloride monohydrate

Polysorbate 80

Sucrose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial3 years.

Chemical and physical in-use stability after opening the vial, including storage in prepared syringes,has been demonstrated for 7 days at 2 °C to 8 °C and 24 hours at up to 30 °C.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 °C to 8 °C, unless preparation has taken place incontrolled and validated aseptic conditions.

Store in a refrigerator (2 °C to 8 °C).

Do not freeze.

Store in the original carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

ELREXFIO 40 mg/mL solution for injection1.1 mL solution in a vial (Type 1 glass) with a stopper (butyl rubber) and an aluminium seal with aflip-off cap containing 44 mg of elranatamab.

Pack size of 1 vial.

ELREXFIO 40 mg/mL solution for injection1.9 mL solution in a vial (Type 1 glass) with a stopper (butyl rubber) and an aluminium seal with aflip-off cap containing 76 mg of elranatamab.

Pack size of 1 vial.

ELREXFIO 40 mg/mL solution for injection is supplied as a ready-to-use solution that does not needdilution prior to administration. Do not shake.

ELREXFIO is a clear to slightly opalescent, and colourless to pale brown solution. The solutionshould not be administered if it is discoloured or contains particulate matter.

Aseptic technique should be used to prepare and administer ELREXFIO.

ELREXFIO 40 mg/mL solution for injection vials are for single use only.

ELREXFIO should be prepared following the instructions below (see Table 9) depending on therequired dose. It is suggested to use a 44 mg/1.1 mL (40 mg/mL) single dose vial for each one of thestep-up doses.

Table 9. Preparation instructions for ELREXFIO

Required dose Dose volume12 mg (Step-up dose 1) 0.3 mL32 mg (Step-up dose 2) 0.8 mL76 mg (Full treatment dose) 1.9 mL

The vial and any remaining contents should be discarded after a single use. Any unused medicinalproduct or waste material should be disposed of in accordance with local requirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/23/1770/001

EU/1/23/1770/002

Date of first authorisation: 07 December 2023

Date of latest renewal: 08 September 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.